Marine organisms are proving to be very productive sources of new therapeutic agents. Indeed, some of today's most promising anticancer drugs in clinical or preclinical trials have been isolated from marine invertebrates or their associated microbes. (Flam, F. 1994. Chemical prospectors scour seas for promising drugs. Science 266:1324-1325; Pettit, G. R. 1994. Marine animal and terrestrial plant anticancer constituents. Pure & Appl. Chem. 66:2271-2281). The spongistatins are a family of macrocyclic lactone polyethers recently isolated from marine Porifera. Spongistatins 1-3 were discovered in Eastern Indian Ocean Spongia sp. (Pettit, G. R., Z. A. Cichacz, F. Gao, C. L. Herald, and M. R. Boyd. 1993). Isolation and structure of the remarkable human cancer cell growth inhibitors spongistatins 2 and 3 from an Eastern Indian Ocean Spongia sp. J. Chem. Soc. Chem. Commun. 14:1166-1168; Pettit, G. R., Z. A. Cichacz, C. L. Herald, M. R. Boyd, J. M. Schmidt, and J. N. A. Hooper. 1993. Isolation and structure of spongistatin 1. J. Org. Chem. 58:1302-1304), and spongistatins 4-7 in the Southeast African marine sponge, Spirastrella spinispirulifera. (Pettit, G. R., C. L. Herald, Z. A. Cichacz, F. Gao, M. R. Boyd, N. D. Christie, and J. M. Schmidt. 1993. Antineoplastic agents 293. The exceptional human cancer cell growth inhibitors spongistatins 6 and 7. Nat. Prod. Lett. 3:239-244; Pettit, G. R., Z. A. Cichacz, F. Gao, J. M. Schmidt, M. R. Boyd, N. D. Christie, and F. E. Boettner. 1993. Isolation and structure of the powerful human cancer cell growth inhibitors spongistatins 4 and 5 from an African Spirastrella spinispirulifera (Porifera). J. Chem. Soc. Chem. Commun. 24:1805-1807). All of the spongistatins have exceptionally potent and selective inhibitory activity against a subset of the U.S. National Cancer Institute's human cancer cell lines. (Pettit, G. R., Z. A. Cichacz, F. Gao, C. L. Herald, and M. R. Boyd. 1993. Isolation and structure of the remarkable human cancer cell growth inhibitors spongistatins 2 and 3 from an Eastern Indian Ocean Spongia sp. J. Chem. Soc. Chem. Commun. 14:1166-1168; Pettit, G. R., Z. A. Cichacz, C. L. Herald, M. R. Boyd, J. M. Schmidt, and J. N. A. Hooper. 1993. Isolation and structure of spongistatin 1. J. Org. Chem. 58:1302-1304; Pettit, G. R., C. L. Herald, Z. A. Cichacz, F. Gao, M. R. Boyd, N. D. Christie, and J. M. Schmidt. 1993. Antineoplastic agents 293. The exceptional human cancer cell growth inhibitors spongistatins 6 and 7. Nat. Prod. Lett. 3:239-244; and Pettit, G. R., Z. A. Cichacz, F. Gao, J. M. Schmidt, M. R. Boyd, N. D. Christie, and F. E. Boettner. 1993. Isolation and structure of the powerful human cancer cell growth inhibitors spongistatins 4 and 5 from an African Spirastrella spinispirulifera (Porifera). J. Chem. Soc. Chem. Commun. 24:1805-1807).
The isolation and elucidation of spongistatins 1-7 are described in U.S. Pat. Nos. 5,328,929 (2, 3, 4 & 6), 5,393,897 (5 and 7 inter alia), and 5,436,400 (1).
Because of their availability, it was of interest to determine whether these macrocyclic lactones might also have other interesting therapeutic activity. The increase in antibiotic resistant microbes and our paucity of effective antifungals, in addition to a growing population of immunocompromised patients, indicated a critical need for novel antimicrobial agents and it was with this goal in mind that we discovered the antifungal activity of the spongistatins.